Glycans of glycoconjugates adorn cell surfaces with recognition elements for sugar-binding proteins (lectins) to mediate functions such as cell-cell recognition and adhesion, initiation of signaling, delivery and routing, also relevant for immune recognition. Multivalent glycan displays are essential to overcome the weak interactions between individual sugars and proteins in order to generate ligand selectivity to sugar-binding protein receptors. In addition to the structure of the glycans, the spatial mode of presentation, its dynamics, and adaptability play a salient role in turning glycan presence into ligand or counter-receptor functionality. The goal of understanding the route to specific recognition and control of cell physiology explains the chemical efforts toward tailoring diverse multivalent glycoconjugate displays accomplished via multivalent scaffolds. Mimics of natural glycoconjugates (glycoproteins and glycolipids) include glycopeptides, glycopolymers, glycodendrimers, glycoliposomes and synthetic glycolipids, cyclic clusters such as cyclophenes, and glycodynamers. Their availability facilitates experimental approaches to understand the functioning of complex assemblies such as microdomains in membranes and can also form the basis for potential medical applications such as blocking undesired lectin binding in inflammation/tumor progression or in infection, or stimulating the immune response by vaccination. Glycopolymers, glycodynamers and glycodendrimers provide some accessible mimics for the biodisplay of glycans but all require complex multistep synthesis to generate multivalency and are often build on toxic scaffolds. Vesicles presenting carbohydrates are more similar to biological cell membrane but lack precise structure since are prepared by co-assembly of several components by hydration followed by multiple fractionation via extrusion. This results in a random distribution of carbohydrates over the surface of vesicle. Therefore, a simple route to hard and soft vesicles that are fully programmable in regards to ligand density and type is in demand. Additions to the existing panel of glycoconjugates that mimic biological membranes will broaden their range of applications.
Recently, we reported a new class of amphiphiles called Janus dendrimers that self-assemble by simple injection of their ethanol solution in water into narrow size distribution and stable in time vesicles called dendrimersomes (Percec, V., et al., Science 2010, 328, 1009-1014). Moving toward applicability, we report here a simple strategy to an accelerated modular synthesis of the first examples of amphiphilic Janus glycodendrimers containing two identical carbohydrates in their hydrophilic part. They self-assemble by simple injection of their solution made in water miscible solvents such as THF and ethanol into water and buffer and by hydration, in unilamellar hard and soft spherical, polygonal and tubular vesicles, a,b, denoted glycodendrimersomes, aggregates of rod-like micelles9a, named glycodendrimermicelles, aggregates of Janus glycodendrimers named glycodendrimer aggregates or for short dendrimer aggregates, cubosomes, denoted glycodendrimercubosomes, as well as hard lamellae. By analogy with dendrimersomes and other complex architectures reported to self-assemble from simple amphiphilic Janus dendrimers, all supramolecular assemblies generated in water from Janus glycodendrimers are obtained with a predictable size that amplifies the multivalency of presentation of their sugars from 2 to n, display narrow molecular mass distribution that in the case of vesicles and liposomes is considered to be monodisperse, 12k and are stable over time. Structurally, they provide models for biological cell membranes with the typical glycan presence on their surface. These assemblies are of general interest as platforms for glycan ligand presentation since they offer a simple supramolecular approach to simulate the naturally multivalent display of carbohydrates. They also may be engineered into devices used in the lectin-mediated delivery of drugs, genes, imaging agents, of pharmaproteins used as therapeutics to block lectins and to act as vaccines targeting lectins on dendritic cells. The spherical nature of the supramolecular assemblies produced from self-assembling amphiphilic Janus glycodendrimers provides an additional advantage to covalent glycodendrimers4 as mimics, since their synthesis is simple and their water cavity can be exploited. Glycodendrimersomes offer an additional advantage to glycodendrimers, by providing mimics of the biological membranes rather than only modeling their surface. Therefore, they are expected, of being not only delivery devices but, to serve the same functions as covalent glycodendrimers. To prove bioactivity in binding to lectins and thereby in principle access the potential applications mentioned above, we demonstrate selective agglutination of glycodendrimersomes of different size with the plant lectin concanavalin A (Con A), the toxic mistletoe lectin Viscum album agglutinin (VAA), a potential biohazard akin to ricin, the bacterial lectin PA-IL from Pseudomonas aeruginosa, and two human lectins members of the galectin family galectin-3, Gal-3, and galectine-4, Gal-4, potently acting in adhesion, growth regulation and glycan routing.